The 5-year survival statistics for pancreatic cancer patients is extremely dismal at ~5% due to its intrinsic chemo-resistant phenotype and advanced disease status present at time of diagnosis, which speaks to the urgency to develop more effective treatments for pancreatic cancer. The proposed studies aim to address a major challenge in the treatment of pancreatic cancer which is the development of novel drug delivery approaches for overcoming the physical and intrinsic barriers in pancreatic cancers that mediate its highly aggressive, drug-resistant progression. The use of receptor targeted iron-oxide theranostic nanoparticles (IONPs) offers the unique ability to not only serve as drug carriers for therapeutic purposes but also serve as diagnostic tools for the detection of residual and metastatic lesions. In order to enhance drug delivery to the tumor, active targeting of IONPs requires the conjugation of ligands that will bind specifically to the tumor cells, active tumor stroma as well as tumor associated cells, namely macrophages, such as the urokinase plasminogen activator receptor (uPAR). Our preliminary studies indicate an increased intratumoral infiltration of T cells and macrophages in tumor lesions following the treatment with uPAR-targeted theranostic IONP, thus creating an environment for the priming and activation of tumor-specific immunological responses while generating anti-tumor effects by cytotoxic drugs delivered by the nanoparticles. In order for this immunogenic potential to be fully exploited, immunosuppressive barriers mediated by the tumor microenvironment must be appropriately overcome. The systemic administration of monoclonal antibodies (mAbs) specific for the inhibitory molecules CTLA-4 and PD-L1 are clinically proven to reduce tumor-derived immune suppression and enhance tumor-specific immune responses however is associated with immune-related adverse events. Therefore, we propose to investigate uPAR targeted IONPs as a model system in the co-delivery of the chemotherapeutic drug gemcitabine and immune modulatory mAbs directly to the tumor microenvironment. Further, elucidation of the immunological mechanisms mediating the induced therapeutic responses following IONP treatment, specifically the type and quantity of immune cell infiltration, not only provides a more comprehensive assessment of therapeutic efficacy but is critical towards the identification of prognostic factors that are likely correlative with overall and disease-free survival.